The relationship between elevated blood lipids, particularly cholesterol (and especially low-density-lipoprotein cholesterol) and atherosclerosis has been known for many years. More recently, reduction of LDL cholesterol by means of surgery or drugs has been shown to reduce the risk of coronary heart disease. However, the reduction of cardiac events achieved by cholesterol lowering does not correlate well with the relatively small amount of physical regression in the amount of atherosclerotic plaque seen in the coronary arteries following treatment. In addition, relief of angina pectoris (ischemic chest pain) often occurs in a matter of weeks following cholesterol lowering; whereas, documentable changes in the inside diameters of coronary arteries may take years to occur, if they occur at all. The pain associated with angina pectoris is attributable primarily to lactic acid produced when heart muscle cell metabolism occurs in the absence of oxygen. Coronary artery narrowing can limit the amount of blood-transported oxygen that reaches the heart muscle tissue, but, the above observation suggests oxygenation of heart muscle tissue can be improved without increasing blood flow through the coronary vessels.
The way in which changes in blood lipids, such as cholesterol might affect oxygen delivery to heart muscle tissue has remained unclear. There is abundant oxygen in blood. In fact, oxygenated (arterial) blood contains approximately as many molecules of oxygen per 1000 mL as are found in 200 mL of oxygen gas. Almost all (98-99%) of this oxygen is bound to hemoglobin molecules within the red blood cells; the remainder is physically dissolved in plasma and intracellular red blood cell fluid. For oxygen to reach tissues, such as cardiac muscle tissue, oxygen must be released from hemoglobin and then diffuse across the red blood cell membrane into the plasma and from there into tissues. The movement of oxygen across the red blood cell membrane occurs by passive diffusion and is governed by concentration gradients, there is no active membrane transport system for oxygen. Furthermore, the composition of a subject""s red blood cell membrane changes with changes in the subject""s lipid status. Therefore, the red blood cell membrane, the immediate surroundings of the red blood cell (the boundary layer), or the contours of the red blood cell membrane can be a significant barrier to release of oxygen into tissue such as cardiac muscle tissue.
What is needed is a method and apparatus to assess the significance of the red blood cell membrane, the immediate surroundings of the red blood cell (the boundary layer), or the contours of the red blood cell membrane as a hindrance to oxygen transfer from blood to tissues, such as cardiac muscle tissue. Such a method and apparatus would provide a new way to assess heart and circulatory disorders related to oxygen transport, such as angina pectoris; a new way to measure, and to assess the impact of, factors that affect oxygen transport from a red blood cell, such as a patient""s blood lipid levels; and a new way to monitor the effectiveness of lipid-lowering therapies or therapies for improving oxygen transport.
The present invention relates to an apparatus and method for determining the rate at which oxygen crosses the red blood cell membrane. The apparatus and method provide a way to assess heart and circulatory disorders related to oxygen transport. Advantageously, the apparatus and method of the invention can be used to assess a patient""s susceptibility to angina pectoris, to determine a patient""s blood lipid levels, to measure factors that affect oxygen transport from a red blood cell, and a new way to monitor the effectiveness of lipid-lowering therapy or therapy for improving oxygen transport.
The present method of measures a rate or rates of oxygen diffusion across a red blood cell membrane from the patient. Advantageously, red blood cell samples are standardized to generally uniform conditions of gas content by exposing the red blood cell to oxygen and exposing the red blood cell to an environment depleted of oxygen as part of the measurement process. Preferably, the rate at which oxygen moves across the red blood cell membrane or its boundary layer is determined by monitoring either a blood plasma level of oxygen, a level of oxygen bound to hemoglobin, or both.
The present method of determining a patient""s blood lipid level, and its impact, includes measuring a rate or rates of oxygen diffusion across a red blood cell membrane from the patient. The rate indicates the blood lipid level, for example, through correlating a measured rate with a previously determined rate or range of rates for an established level of blood lipid. Advantageously, red blood cell samples are standardized to generally uniform conditions of gas content by exposing the red blood cell to oxygen and exposing the red blood cell to an environment depleted of oxygen as part of the measurement process. Preferably, the rate at which oxygen moves across the red blood cell membrane is determined by monitoring either a blood plasma level of oxygen, a level of oxygen bound to hemoglobin, or both.
In one embodiment, the method of the invention can be used to assess a patient""s susceptibility to angina pectoris. This embodiment includes measuring a rate of oxygen diffusion across a membrane of a red blood cell from the patient. This rate indicates the patient""s susceptibility to angina pectoris, for example, by correlating the measured rate with the susceptibility to angina observed in a control or standardized population, or in the patient, at the measured rate.
In another embodiment, the method of the invention can be used to follow the course of a lipid-lowering therapy. This embodiment includes measuring a rate of oxygen diffusion across a membrane of a red blood cell from the patient. This rate determines the effectiveness of a lipid-lowering therapy, for example, by correlating the measured rate with lipid levels to determine the patient""s relative or absolute lipid level, and comparing the patient""s lipid level to the patient""s previous lipid levels.
The apparatus of the invention, which is suitable for conducting the methods of the invention, measures diffusion of oxygen across a red blood cell membrane and includes an oxygen level detector, a gas exchange system, and a red blood cell transport system. The red blood cell transport system is adapted and configured for transporting red blood cells through the gas exchange system and the oxygen level detector. The gas exchange system is adapted and configured to exchange gasses with the red blood cell. The oxygen level detector is adapted and configured for detecting oxygen levels in a red blood cell or in fluid (e.g., plasma) surrounding a red blood cell.
In a preferred embodiment of the apparatus, the oxygen level detector is a spectrophotometric detector, the red blood cell transport system is a pump, and the gas exchange system is a closed loop diffusion system. The preferred closed loop diffusion system includes gas permeable tubing in a chamber defined by a housing. The gas permeable tubing has a lumen effective for containing red blood cells and for diffusion of gas through the tubing and to and the red blood cells. The housing is adapted and configured for containing successive samples of gases to effect gas exchange with the red blood cells.